title: Host genetic background impacts modulation of the TLR4 pathway by RON in tissue-associated macrophages.
abstract: Toll-like receptors (TLRs) enable metazoans to mount effective innate immune responses to microbial and viral pathogens, as well as to endogenous host-derived ligands. It is understood that genetic background of the host can influence TLR responsiveness, altering susceptibility to pathogen infection, autoimmunity and cancer. Macrophage stimulatory protein (MSP), which activates the receptor tyrosine kinase recepteur d'origine nantais (RON), promotes key macrophage functions such as motility and phagocytic activity. MSP also acts via RON to modulate signaling by TLR4, which recognizes a range of pathogen or endogenous host-derived molecules. Here, we show that RON exerts divergent control over TLR4 activity in macrophages from different mouse genetic backgrounds. RON potently modulated the TLR4 response in macrophages from M2-prone FVB mice, as compared with M1-skewed C57Bl6 mice. Moreover, global expression analysis revealed that RON suppresses the TLR4-dependent type-I interferon gene signature only in FVB macrophages. This leads to attenuated production of the potent inflammatory mediator, tumor necrosis factor-α. Eliminating RON kinase activity markedly decreased carcinogen-mediated tumorigenesis in M2/Th2-biased FVB mice. We propose that host genetic background influences RON function, thereby contributing to the variability in TLR4 responsiveness in rodents and, potentially, in humans. These findings provide novel insight into the complex interplay between genetic context and immune function.
authors.affiliation: Department of Molecular Oncology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Amitabha
authors.initials: A
authors.lastname: Chaudhuri
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Wilson
authors.forename: Becky
authors.initials: B
authors.lastname: Yang
authors.forename: Andres
authors.initials: A
authors.lastname: Paler Martinez
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Liu
authors.forename: Catherine
authors.initials: C
authors.lastname: Zhu
authors.forename: Nicole
authors.initials: N
authors.lastname: Bricker
authors.forename: Suzana
authors.initials: S
authors.lastname: Couto
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Dorothy
authors.initials: D
authors.lastname: French
authors.forename: James
authors.initials: J
authors.lastname: Cupp
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000008:administration & dosage; D000818:Animals; D063646:Carcinogenesis; D002465:Cell Movement / Q000187:drug effects; D005354:Fibrosarcoma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D005838:Genotype; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology*; D008748:Methylcholanthrene / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D058408:Th1-Th2 Balance; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D015533:Transcriptional Activation / Q000235:genetics; D059467:Transcriptome
chemical_list: D007370:Interferon Type I; D011518:Proto-Oncogene Proteins; D051197:Toll-Like Receptor 4; C082332:macrophage stimulating protein; D008748:Methylcholanthrene; D015127:9,10-Dimethyl-1,2-benzanthracene; D017228:Hepatocyte Growth Factor; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases